A major barrier to HIV eradication is the existence of a small pool of long-lived latently-infected, resting memory CD4[+] T cells carrying an integrated form of the viral genome. Memory T cells encompass a variety of cell subsets all endowed with specific survival and differentiation properties. We have recently demonstrated that the privileged cell type where HIV establishes its resen/oir is the central memory T cell (T{CM}) and its immediate progeny, the transitional memory T cell (T{TM})- IL-7 is one of the cytokines that is responsible for sustaining low levels of proliferation in T{CM} and T{TM}. Harnessing IL-7 interactions with its receptor on TCM could provide a strategy to prevent the survival and proliferation of these cells, and to prevent the persistence of the HIV reservoir. Another cytokine known to play a major role in memory T cell survival is IL-15. We have recently demonstrated that IL-15 engagement with its receptor on resting CD4[+] T{CM} that harbor latent virus will induce their differentiation into short-lived effector memory T cells (T{EM}) that can proliferate and produce virus. We propose to exploit this capacity of IL-15 so that the pool of resting, infected T{CM} cells can be depleted in vitro and in vivo. We will first determine the relative impact of IL-7 and IL-15 on HIV persistence in vivo and in vitro by measuring the contribution of these cytokines to the maintenance of the pool of latently infected cells in blood and tissues obtained from subjects receiving suppressive ART and by evaluating their capacity to induce viral reactivation (Specific Aim 1). We will then test the hypothesis that blocking the IL-7 pathway or, conversely, administrating IL-15 to optimally-treated macaques could be used as strategies to deplete the latent viral reservoir (Specific Aim 2). Our proposed interventions target the major cellular source of persistent virus during treatment, and although they may not work alone in eradicating HIV, they could complement other interventions by transiently reversing the host factors that are critical in maintaining latently infected cells.

Public Health Relevance

Eradication of HIV has been the focus of several clinical interventions that unfortunately have failed to reach their goal. Most of these strategies have relied on the use of complex antiviral regimens to test the hypothesis that eradication of HIV can be achieved by inhibiting the residual viral replication in CD4[+] T cells or in other compartments. In this project, we will focus on those host factors that contribute to maintanece of latency and which could be reversed using targeted therapeutic strategies.

Agency
National Institute of Health (NIH)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI096109-04
Application #
8703596
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
Stevenson, Mario (2015) Role of myeloid cells in HIV-1-host interplay. J Neurovirol 21:242-8
Dunham, Richard M; Vujkovic-Cvijin, Ivan; Yukl, Steven A et al. (2014) Discordance between peripheral and colonic markers of inflammation during suppressive ART. J Acquir Immune Defic Syndr 65:133-41
Ribeiro, Susan P; Milush, Jeffrey M; Cunha-Neto, Edecio et al. (2014) The CD8? memory stem T cell (T(SCM)) subset is associated with improved prognosis in chronic HIV-1 infection. J Virol 88:13836-44
Stock, P G; Barin, B; Hatano, H et al. (2014) Reduction of HIV persistence following transplantation in HIV-infected kidney transplant recipients. Am J Transplant 14:1136-41
Bullen, C Korin; Laird, Gregory M; Durand, Christine M et al. (2014) New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo. Nat Med 20:425-9
Dahl, Viktor; Peterson, Julia; Fuchs, Dietmar et al. (2014) Low levels of HIV-1 RNA detected in the cerebrospinal fluid after up to 10 years of suppressive therapy are associated with local immune activation. AIDS 28:2251-8
Gray, Lachlan R; Roche, Michael; Flynn, Jacqueline K et al. (2014) Is the central nervous system a reservoir of HIV-1? Curr Opin HIV AIDS 9:552-8
Kim, Michelle; Hosmane, Nina N; Bullen, C Korin et al. (2014) A primary CD4(+) T cell model of HIV-1 latency established after activation through the T cell receptor and subsequent return to quiescence. Nat Protoc 9:2755-70
Cockerham, Leslie R; Jain, Vivek; Sinclair, Elizabeth et al. (2014) Programmed death-1 expression on CD4? and CD8? T cells in treated and untreated HIV disease. AIDS 28:1749-58
Anderson, Jenny L; Cheong, Karey; Lee, Amas K H et al. (2014) Entry of HIV in primary human resting CD4(+) T cells pretreated with the chemokine CCL19. AIDS Res Hum Retroviruses 30:207-8

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